1. Field of the Invention
The present invention refers to an improved method of producing 5-formyl-2-furylboronic acid.
2. Discussion of the Background
The Suzuki coupling reaction is a well known method for the formation of aryl-aryl bonds, whereby an aryl borate is reacted with an aryl halide in a palladium catalyzed coupling reaction. The Suzuki coupling reaction is very useful in the synthesis of drugs and consequently it is under current investigation to provide suitable starting materials.
One very useful building block is 5-formyl-2-furylboronic acid. Florentin et al. (Bull. Soc. Chim. Fr. 1976, 11–12, 1999) discloses the preparation of 5-formyl-2-furylboronic acid starting from 2-furaldehyde. The formyl functionality of the 2-furaldehyde is protected as diethylacetal and said diethylacetal is metalated with methyllithium. The obtained lithiated furan is subsequently reacted with tributyl borate and after acidic quench the 5-formyl-2-furylboronic acid was isolated. Florentin et al. investigated the 1H and 13C NMR spectra of said furylboronic acid. There is no further disclosure regarding the reaction conditions, yield or purity of the obtained 5-formyl-2-furylboronic acid.
In an earlier paper, Florentin et al. (C.R.Acad.Sc.Paris, Ser. C 1970, 270, 1608) describes the preparation of 5-formyl-2-furylboronic acid by metalation of 2-formyl-5-bromofuran with butyl lithium and subsequent reaction of the metalated furan derivative with n-butylborate. After acidic work-up the 5-formnyl-2-furylboronic acid was obtained as white crystals in a 15% yield.
WO96/16046 describes the synthesis of 5-formyl-2-furylboronic acid whereby furfuraldiethylacetal is metalated with butyl lithium in ether as a solvent at a temperature of −40° C. The reaction mixture is stirred at room temperature for additional 2 hours and subsequently again chilled to −40° C. A solution of trimethylborate in ether is added and subsequently heated to room temperature and then held at reflux. After acidic work-up and recrystallization 5-formyl-2-furylboronic acid was isolated as a colorless solid in 26% yield.
McClure (Synthesis 2001, No.11, 1681–1685) describes a practical one-pot synthesis of 5-aryl-2-furaldehyde via palladium mediated Suzuki coupling of arylhalides with in situ generated 5-(diethoxymethyl)-2-furylboronic acid. 5-(Diethoxymethyl)-2-furylboronic acid is used as building block because 5-formyl-2-furylboronic acid is considered to be cost-prohibitive and the described preparation methods of same suffer from low temperature requirements, capricious reproducibility, tedious work-up as well as unsuitably low purity and isolated yields. McClure was not able to improve the isolation of 5-(diethoxymethyl)-2-furylboronic acid as well as 5-formyl-2-furylboronic acid and therefore decided to use a crude solution of 5-(diethoxymethyl)-2-furylboronic acid in the subsequent Suzuki coupling.
Roschangar et al. (Tetrahedron 58 (2002) 1657–1666) describes the preparation of 5-formyl-2-furylboronic acid, whereby starting from furfural said boronic acid is obtained via metalation and subsequent addition of triisopropylborate to the metalated furan derivative. Because of the difficulties described in the prior art like low temperature requirements, capricious reproducibility, tedious workup as well as unsuitably low purity and isolated yields Roschangar et al. did not try to isolate 5-formyl-2-furylboronic acid. Therefore, they applied the boronic acid to a subsequent Suzuki coupling without further purification. 5-Formyl-2-furylboronic acid was obtained as crude reaction solution, only.